Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors

Simon Giroux; Jinwang Xu; T Jagadeeswar Reddy; Mark Morris; Kevin M Cottrell; Caroline Cadilhac; James A Henderson; Oliver Nicolas; Darius Bilimoria; Francois Denis; Nagraj Mani; Nigel Ewing; Rebecca Shawgo; Lucille L'Heureux; Subajini Selliah; Laval Chan; Nathalie Chauret; Francoise Berlioz-Seux; Mark N Namchuk; Anne-Laure Grillot; Youssef L Bennani; Sanjoy K Das; John P Maxwell

doi:10.1021/ml300461f

Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors

ACS Med Chem Lett. 2013 Jan 27;5(3):240-3. doi: 10.1021/ml300461f. eCollection 2014 Mar 13.

Authors

Simon Giroux¹, Jinwang Xu¹, T Jagadeeswar Reddy², Mark Morris¹, Kevin M Cottrell¹, Caroline Cadilhac², James A Henderson¹, Oliver Nicolas², Darius Bilimoria², Francois Denis², Nagraj Mani¹, Nigel Ewing¹, Rebecca Shawgo¹, Lucille L'Heureux², Subajini Selliah², Laval Chan², Nathalie Chauret², Francoise Berlioz-Seux¹, Mark N Namchuk¹, Anne-Laure Grillot¹, Youssef L Bennani², Sanjoy K Das², John P Maxwell¹

Affiliations

¹ Vertex Pharmaceuticals Incorporated , 130 Waverly Street, Cambridge, Massachusetts 02139, United States.
² Vertex Pharmaceuticals Canada Incorporated , 275 Boul. Armand-Frappier, Laval, QC, H7V 4A7, Canada.

Abstract

The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.

Keywords: HCV; NS5A; thienoimidazoles.